Retrospectively diagnosed autoimmune VWF deficiency in a patient with repeated hemorrhagic events after two common colds.

Autoimmune von Willebrand factor (VWF) deficiency (AiVWFD) caused by anti-VWF autoantibodies is a rare bleeding disorder, whereas "non-immune" acquired von Willebrand syndrome (AVWS) caused by other etiologies is more common. Therefore, only 40 patients with AiVWFD have been identified in Japan through an ongoing nationwide survey on autoimmune coagulation factor deficiencies. This may be due to the inability to efficiently detect anti-VWF antibodies, as anti-VWF antibody testing is not routine. An 80-year-old Japanese woman developed AVWS and experienced bleeding after two separate common colds. She took the same cold medicine each time and recovered spontaneously after discontinuation of the medicine. Severe VWF deficiency normalized each time. Initial immunological tests did not detect anti-VWF autoantibodies, and thus a diagnosis of "non-immune" AVWS of unknown origin was made. However, after 6 years, new ELISA assays using purified VWF proteins detected free anti-VWF autoantibodies, which led to a retrospective diagnosis of AiVWFD. It is probable that the cold medicine (and/or cold virus infection) induced the autoantibodies, as the recurrence and normalization of the same coagulation abnormality and the clinical course (including drug administration and discontinuation) were completely synchronized. If AiVWFD is suspected, highly sensitive autoantibody tests should be performed.

Laparoscopic hepatectomy for hepatocellular carcinoma in patients with hemophilia A and B: a report of two cases.

Hepatocellular carcinoma (HCC) is a life-threatening complication of hemophilia. Reports of patients with hemophilia undergoing hepatectomy for HCC are scarce. We report the cases of patients with hemophilia A and B who underwent laparoscopic hepatectomy for HCC. Perioperative hemophilia management was supervised by the hematology team. The patients received coagulation factor bolus injections immediately preoperatively, then continuous intravenous infusions intra- and postoperatively. A laparoscopic segment II partial hepatectomy was performed in case 1. Due to severe adhesions, intermittent pedicle clamping could not be used during parenchymal transection. The surgical duration was 235 min, and the estimated blood loss was 13 mL. The patient was discharged 11 days postoperatively without any complications. In case 2, laparoscopic partial hepatectomy for segments V/VI was performed. An intermittent pedicle clamp (Pringle method) was used during parenchymal transection. The surgical duration and estimated blood loss were 219 min and 18 mL, respectively. The patient was discharged 8 days postoperatively without complications. In both cases, intraoperative bleeding was minimal, and the patients were discharged without postoperative hemorrhage with appropriate perioperative coagulation factor management. Laparoscopic hepatectomy can be safely performed and appears to be a feasible treatment option for HCC in patients with hemophilia.

Pilot study of aerosols visualized and evaluated in a radiotherapy room.

Health care institutions provide prevention strategies for coronavirus disease 2019 and non-infectious disease care. We investigated the characteristics of patient contamination in a radiotherapy room by examining the trajectory and number of airborne particles in the air when talking and coughing occurred and clarified the actual state of contamination in this closed space. Aerosols were visualized and evaluated in the vertical height and head-to-tail width directions when the participant was lying on the radiotherapy tabletop. Aerosol reach was significantly greater for loud voice and coughing both at vertical height and the head-to-tail width direction. The size and number of particles around the radiotherapy tabletop were also visualized and evaluated in the radiotherapy room. The radiotherapy staff who were in the presence of the participant sometimes had many particles adhering to their facial area; particle adhesion to the staff was dominated by small size particles. Particle adherence to the irradiation device surface near the ceiling had particles larger than 1 mm. Tabletop particles tended to have a wider size range, including bigger sizes and a larger count compared to the surrounding floor. The 0.7-m radius distance from the participant's mouth tended to be highly contaminated, and the smaller the particle size, the farther it reached. The capacity to estimate areas prone to contamination can be used to predict infection of other patients and medical staff in a radiotherapy room.

The Assessment of the Efficacy and Safety of Favipiravir for Patients with SARS-CoV-2 Infection: A Multicenter Non-randomized, Uncontrolled Single-arm Prospective Study.

Objective Among treatment options for coronavirus infectious disease 2019 (COVID-19), well-studied oral medications are limited. We conducted a multicenter non-randomized, uncontrolled single-arm prospective study to assess the efficacy and safety of favipiravir for patients with COVID-19. Methods One hundred participants were sequentially recruited to 2 cohorts: cohort 1 (Day 1: 1,600 mg/day, Day 2 to 14: 600 mg/day, n=50) and cohort 2 (Day 1: 1,800 mg/day, Day 2 to 14: 800 mg/day, n=50). The efficacy endpoint was the negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the odds ratio (OR) of cohort 2 to cohort 1 for negative conversion on Day 10 was calculated. Characteristics of all participants and profiles of adverse events (AEs) were collected and analyzed. Results The mean age of participants was 62.8±17.6 years old. Thirty-four patients (34.0%) experienced worsening pneumonia, 7 (7.0%) were intubated, and 4 (4.0%) died during the observation period. Cohort 2 showed a higher negative conversion rate than cohort 1 [adjusted OR 3.32 (95% confidence interval (CI), 1.17 to 9.38), p=0.024], and this association was maintained after adjusting for the age, sex, body mass index, and baseline C-reactive protein level. Regarding adverse events, hyperuricemia was most frequently observed followed by an elevation of the liver enzyme levels (all-grade: 49.0%, Grade ≥3: 12.0%), and cohort 2 tended to have a higher incidence than cohort 1. However, no remarkable association of adverse events was observed between patients <65 and ≥65 years old. Conclusion The antiviral efficacy of favipiravir was difficult to interpret due to the limitation of the study design. However, no remarkable issues with safety or tolerability associated with favipiravir were observed, even in elderly patients with COVID-19.

Serological Screening of Immunoglobulin G against SARS-CoV-2 Nucleocapsid and Spike Protein before and after Two Vaccine Doses among Healthcare Workers in Japan.

This study sought to evaluate the effects of two vaccine doses and the extent of SARS-CoV-2 infection among healthcare workers. We measured immunoglobulin G antibody titers against SARS-CoV-2 nucleocapsid and spike protein among healthcare workers at Gunma University Hospital. In March 2021, prior to BNT-162b2 vaccination, two of 771 participants were seropositive for nucleocapsid and spike protein, whereas 768 were seronegative. The remaining one participant was seropositive for nucleocapsid protein but seronegative for spike protein. A total of 769 participants were seropositive for spike protein after two vaccination doses. The two seropositive participants prior to vaccination showed the highest antibody titers after the second vaccination. They were probably infected with SARS-CoV-2 without clinical symptoms before March 2021. Four weeks after the second vaccination, a younger age was associated with higher antibody titers against SARS-CoV-2 spike protein. Thirty-two weeks after the second vaccination, blood samples were collected from 342 of 769 participants. Antibody titers at 32 weeks after the second vaccination significantly decreased compared with those at 4 weeks after the second vaccination among all age groups. The rate of decrease in antibody titers between 4 and 32 weeks after the second vaccination was greater in the female participants. No sex differences were observed in the antibody titers within each age group. BNT-162b2 vaccination thus induced seroconversion in an age-dependent manner. Serological screening could further establish the likelihood of subclinical SARS-CoV-2 infection.

Successful treatment of Japanese hemophilia patient co-infected with HIV and HCV genotype 4a by glecaprevir/pibrentasvir therapy.

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.

Erythema nodosum-like eruption in coronavirus disease 2019: A case report and literature review of Asian countries.

In the worldwide coronavirus disease 2019 (COVID-19) outbreak, skin manifestations were seen in COVID-19 patients. We report a case in which a COVID-19 patient developed cutaneous lesions that were diagnosed as erythema nodosum-like lesions, which were associated with COVID-19. Nasopharyngeal swab polymerase chain reaction (PCR) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathologically, extensive inflammation was seen from the epidermis to the fat tissue. An organized thrombus and disrupted inner elastic lamina were seen in an intradermal vessel. These findings suggest septal panniculitis with cutaneous polyarteritis nodosa. The results of PCR using the specimen of skin lesion was negative. The patient took non-steroidal anti-inflammatory drugs and the skin lesion improved in 3 weeks. To characterize the skin eruption, we reviewed previous reports on COVID-19 (confirmed by the detection of SARS-CoV-2 infection) from Asian countries. The type of eruption and timing of its appearance in this case seemed rare. Differences in skin manifestations between Western and Asian countries were noted.

Deficiency of mannose-binding lectin is a risk of Pneumocystis jirovecii pneumonia in a natural history cohort of people living with HIV/AIDS in Northern Thailand.

BACKGROUND: Mannose-binding lectin (MBL) plays a pivotal role in innate immunity; however, its impact on susceptibility to opportunistic infections (OIs) has not yet been examined in a natural history cohort of people living with HIV/AIDS. METHODS: We used archived samples to analyze the association between MBL expression types and risk of major OIs including Pneumocystis jirovecii pneumonia (PCP), cryptococcosis, talaromycosis, toxoplasmosis, and tuberculosis in a prospective cohort in Northern Thailand conducted from 1 July 2000 to 15 October 2002 before the national antiretroviral treatment programme was launched. RESULTS: Of 632 patients, PCP was diagnosed in 96 (15.2%) patients, including 45 patients with new episodes during the follow-up period (1006.5 person-years). The total history of PCP was significantly associated with low MBL expression type: high/intermediate (81/587, 13.8%), low (10/33, 30.3%) and deficient (5/12, 41.7%) (p = 0.001), whereas the history of other OIs showed no relation with any MBL expression type. Kaplan-Meier analysis (n = 569; log-rank p = 0.011) and Cox's proportional hazards model revealed that deficient genotype dramatically increased the risk of PCP, which is independent upon sex, age, CD4 count, HIV-1 viral load and hepatitis B and C status (adjusted hazard ratio 7.93, 95% confidence interval 2.19-28.67, p = 0.002). CONCLUSIONS: Deficiency of MBL expression is a strong risk factor determining the incidence of PCP but not other major OIs.

Improvement of Severe COVID-19 in an Elderly Man by Sequential Use of Antiviral Drugs.

Although a variety of existing drugs are being tested for patients with coronavirus disease 2019 (COVID-19), no efficacious treatment has been found so far, particularly for severe cases. We report successful recovery in an elderly patient with severe pneumonia requiring mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Despite administration of multiple antiviral drugs, including lopinavir/ritonavir, chloroquine, and favipiravir, the patient's condition did not improve. However, after administration of another antiviral drug, remdesivir, we were able to terminate invasive interventions, including ECMO, and subsequently obtained negative polymerase chain reaction results. Although further validation is needed, remdesivir might be effective in treating COVID-19.

[Successful management of acquired factor V deficiency developing shortly after induction of hemodialysis].

Autoimmune factor V deficiency (AiF5D) is caused by autoantibodies to coagulation factor V (FV); its clinical manifestations range from asymptomatic to fatal hemorrhage. Herein, we report the case of a 68-year-old man who was diagnosed with end-stage renal disease at the time of a femoral fracture and developed AiF5D after initiating hemodialysis. A wound infection that occurred after joint replacement was treated with antibiotics; however, it was poorly controlled. One month after the procedure, his coagulation time prolonged. The infection was improved by debridement and antibiotics; however, the coagulation time was not decreased and poor hemostasis at the shunt was still persistent. Because ELISA detected anti-FV-binding IgG with FV activity of <2.8% and FV inhibitor levels were 11.8 BU/ml, AiF5D was diagnosed. Oral prednisolone (PSL) was started. Dialysis was initially performed without anticoagulants, but blood clots were not found in the circuit. Anticoagulants were resumed when the coagulation time decreased. After achieving complete remission, PSL dose was tapered and finally discontinued. Few reports have described the management of AiF5D via dialysis. We consider that our report would be useful for the management of patients with similar manifestations.

IgG4-related Disease with a Cardiac Mass.

A 69-year-old man with palpitations and decreased blood pressure was referred. Echocardiography showed a mass in the right atrium and cardiac septum. The serum IgG4 level was 1,450 mg/dL. A biopsy of the cardiac mass showed fibrosis with inflammatory cells and increased IgG4-positive plasma cells and lymphocytes. Flow cytometry and polymerase chain reaction of the immunoglobulin heavy chain did not demonstrate monoclonality. He was diagnosed with IgG4-related disease (IgG4-RD). IgG4-RD with a cardiac mass is rare and it is difficult to distinguish it from malignant lymphoma by a pathological examination alone. We therefore performed a biopsy and analyzed the clonality in order to make an accurate diagnosis of IgG4-RD.

Overshoot of FVIII activity in patients with acquired hemophilia A who achieve complete remission.

Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activity (median 2.1%; range < 1.0-8.9%) due to FVIII inhibition (median 14.7 BU/mL; range 2.0-234.0) and all achieved CR within a median of 39 (range 19-173) days. Overshoot occurred in 11 (64.7%) patients and maximal FVIII activity reached > 200% in six of them. The median duration from CR to overshoot was 13 (range 0-154) days. The FVIII overshoot was transient (72.7%) or persistent (27.3%). Venous thromboembolism developed as a complication of overshoot in one patient due to iliac vein compression by a massive hematoma. Overshoot of FVIII activity after CR occurs more frequently than previously expected in patients with AHA.

[Thyroid storm and exacerbation of autoimmune hemolytic anemia following childbirth].

A 32-year-old woman was diagnosed with autoimmune hemolytic anemia (AIHA) at 12 weeks of a pregnancy examination and followed up closely without treatment. At 40 weeks of gestation, she underwent emergency caesarean section because of premature rupture. On postoperative day one, the patient exhibited worsening hemolysis and tachycardia and developed high-output heart failure; she was diagnosed with Basedow disease based on the tachycardia pattern and thyroid storm based on the presence of hyperthyroidism, fever, tachycardia, and heart failure. She was administered thiamazole and potassium iodide, which improved her thyroid function, hemolytic anemia, and heart failure. AIHA is rarely associated with Basedow disease, and hemolytic anemia can be aggravated by hyperthyroidism. In pregnant women with AIHA, management of hyperthyroidism is crucial as delivery can lead to thyroid storm.

[Recurrence of acquired factor V inhibitor after four years of remission].

Acquired factor V inhibitor (AFV-I) is a rare bleeding disorder wherein autoantibodies are developed against coagulation factor V (FV). The clinical symptoms are variable, from laboratory abnormalities without bleeding to life-threatening hemorrhage. We report herein the case of a patient with AFV-I with two relapses 4 years after the first remission. A 66-year-old male was diagnosed with AFV-I in March 20XX-4. He was treated with prednisolone (PSL) at 50 mg/day and achieved remission within 1 month. PSL dose was tapered to oral administration of 2.5 mg every other day, and long-term remission was maintained. He had been treated with dual antiplatelet therapy (DAPT) for old myocardial infarction. FV activity was markedly reduced to 3.4%, and FV inhibitor was detected (1.0 BU/ml) in May 20XX. We followed the patient without increasing the treatment dose for 2 months, but no spontaneous improvement was seen. Because DAPT was ongoing, we judged that the bleeding risk was high, although only minor bleeding symptoms appeared. PSL was therefore increased to 40 mg/day in June. FV inhibitor rapidly disappeared. When PSL dose was gradually decreased, FV activity decreased, and subcutaneous bleeding occurred in February 20XX＋1. PSL dose was increased again for the second relapse, and the patient achieved remission. Few reports have described recurrent AFV-I, and no cases of two relapses have been reported. We believe that this case report is useful for examining the long-term management of AFV-I.

A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.

We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants.

Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients.

PURPOSE: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. METHODS: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. RESULTS: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (- 41.6-23.0% vs - 83.3-109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. CONCLUSIONS: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.

[Congenital factor V and factor VIII deficiency discovered in an elderly patient with abnormal bleeding after trauma].

Congenital combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) (F5F8D) is a rare autosomal recessive bleeding disorder caused by mutations in lectin mannose-binding type 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2) encoding chaperone molecules involved in the intracellular transport of FV and FVIII. Here, we report a case of F5F8D in an elderly patient diagnosed with hematoma after a right thigh injury. A 71-year-old male had a history of abnormal bleeding after tooth extraction and cholecystectomy. The patient injured his right thigh with a kitchen knife; he was urgently hospitalized to a referral hospital 8 days later due to the occurrence of hematoma at the same site. Owing to prolongation of the coagulation time (PT 16.1 s, 1.72; APTT, 66.1 s), he received hemostatic treatment with fresh-frozen plasma. He was then referred to our hospital for examination of PT and APTT prolongation. FV and FVIII activities were moderately decreased to about 15%, and no inhibitor was detected. Whole-exome sequencing identified a previously reported homozygous nonsense mutation in LMAN1, revealing F5F8D in the proband. In this case, FFP infusion alone was not sufficient for increasing coagulation factor activities. Definitive diagnosis of F5F8D provides him with the treatment option with FVIII concentrates.